Molecular genetics of mammalian development, differentiation and oncogenesis. This part of the project contains two approaches. A. Homeobox genes and myc genes. Factors encoded by these families of genes have been implicated in the transcriptional regulation of embryonic development. In situ hybridization of embryonic tissue sections and whole mounts of embryos with polymerase chain reaction analysis have revealed distinct spatial and temporal patterns of expression of several members of these genes. Both the homeobox and the myc gene families are likely to be involved in orchestrating individual facets of early mouse development. Presently, we attempt to introduce defective DNA sequences via homologous recombination into specific target genes of pluripotent mouse embryonic stem cells in an effort to generate mutations in specific chromosomal genes. If successful, this type of experiment will corroborate genetic evidence for the involvement of homeobox, myc, and other gene families in the regulation of mouse development. It can also be used to generate mouse models of human genetic diseases. B. Differentiation and oncogenesis in the eye lens of transgenic mice. We have utilized the simple architecture of the eye lens to develop a model system for the analysis of deregulated growth in the living mammalian organism. Oncogene products of polyoma and SV40 virus released in lens tissue at specific times of mouse development result in distinct lens pathologies. Our findings have allowed us to propose a working model postulating that both timing of expression and the dose of a given oncogene product are of crucial importance for subsequent steps of growth deregulation. Biomedical research. In this part of our project, we have identified the placenta as an organ that is very active in recognizing AIDS virus promoters in the transgenic mouse. This result has important implications for the risk assessment for children born to mothers infected with the human immunodeficiency virus. Also, we have begun to exploit possibilities of producing in milk of transgenic farm animals large amounts of tissue plasminogen activator and of sCD4, human proteins needed to treat coronary diseases and AIDS, respectively.